Oral mucositis is a common side-effect associated with cancer treatment, both with chemotherapy and radiotherapy. Mucositis accounts for significant pain and discomfort for these patients, and ranges in severity from redness and swelling to frank ulcerative lesions. Of primary concern are those patients undergoing: chemotherapy for cancer such as leukemia, breast cancer or as an adjuvant to tumor removal; radiotherapy for head and neck cancer; and combined chemotherapy and radiotherapy for bone marrow transplants. All bone marrow transplant and about half of the head and neck cancer patients develop mucositis (about 10,000 cases/yr and 15,000 cases/yr, respectively). Also, breast cancer patients contemplating extended 5-fluorouracil treatment (about 50,000 cases/yr) would be likely to develop mucositis from such therapy.
Chemotherapeutic agents and radiation can kill or damage the epithelial cells lining the oral cavity. Such damage includes the inhibitory effect that chemotherapeutic agents may have on mitoses of the rapidly dividing cells of the oral basal epithelium. Consequently, the renewal rate of the basal epithelium is reduced, which results in atropic changes of the mucosa and eventually ulceration. The severity of damage is related to the type and dose of chemotherapeutic agent(s) and concomitant therapy such as radiotherapy. Further, ulceration is hastened if sources of chronic irritation such as defective dental restorations, fractured teeth or ill-fitting dental prostheses are present.
Mucositis most often affects the nonkeratinized mucosa of the cheeks, lips, soft palate, ventral surface of the tongue and floor of the mouth, approximately one to two weeks after cancer therapy. The lesions often become secondarily infected and become much harder to heal. At present, there is no effective treatment for mucositis. Therapy is limited to pain medications and treatment of secondary infection. In particular, recommendations have included treatment with topical anesthetics such as xylocaine, benzocaine and cocaine, treatment with solutions which coat the ulcerative lesions with a polysaccharide gel and use of antiseptic solutions such as Chlorhexadine. While all these treatments do provide some relief, none are directed to the actual healing of oral mucositis, which entails directly healing the mucosal epithelium cells.
Treatment of chemotherapy or radiotherapy induced oral mucositis presents some very unique problems. As used herein the term "oral" is used to mean both the oral cavity and the esophagus. First, there is the nature of the mucosal surface itself. As used herein the term "oral mucosa" means the mucocutaneous junction of the lips to include the buccal and labial mucosa, the alveolar mucosa, the floor of the mouth, the dorsal and ventral surfaces of the tongue, the hard and soft palate, the posterior-oropharynx and the esophagus. The histologic architecture of the oral cavity mucosal surface is unique as it is comprised of mucosal squamous epithelium which does not undergo complete cornification. Thus, it is distinct from skin tissue which is cornified squamous epithelial but not mucosal in nature, and from gastric and intestinal tissue which is mucosal but is columnar rather than squamous epithelium. Second, there is the nature of the oral cavity. The mobility and physical action of the tongue markedly decrease the adhesion of any dressing containing a therapeutic agent to the oral cavity surface. The presence of teeth causes constant mucosal trauma. Further, the composition of the saliva is fairly complex, containing for example, numerous enzymes such as lysozyme, amylase and ligase, kallikrein, immunoglobulins, lubricatory molecules such as the parotid prolinerich glycoprotein-albumin complex, zinc-binding proteins such as gustin and mucin glycoproteins. Additionally, there is a unique and dynamic bacterial flora which is affected by the patient's immunologic status. Lastly, there is the physical barrier effect of mucus, which lines the oral mucosal surface and decreases the ability of therapeutic agents to penetrate the epithelial surface. The mucosal tissue and environment of the oral cavity is thus distinguishable from other epithelial surfaces.
This invention pertains to the prevention and treatment of oral mucositis with growth factors. The use epidermal of growth factor in wound healing has been studied extensively in the gastrointestinal tract, including gastic, duodenum, jejunum, ileium and colonic tissue. However, studies done on oral cavity epithelial tissue have been primarily limited to subcutaneous injections of epidermal growth factor to measure the effect on intact mucosa. Steidler et. al, Arch Oral Biol. (1980) 25:37-43. There have been no studies done on wound healing of oral mucosal tissue where the epithelial layer and underlying stromal tissue have been damaged or destroyed as a result of chemotherapy or radiotherapy. Intravenous infusion of granulocyte colony stimulating factor appears to reduce the incidence and severity of oral mucositis in cancer patients. Gabrilove, The New England Journal of Medicine (1988) 318(22):1414-1422. However, the mechanism is likely to be its effect on increasing peripheral white blood cells thereby reducing secondary infection, rather than via growth promoting effects on basal epithelial or stromal cells.